Lecture 2 to 3: PD

Question 1

Drugs affecting Ligand-gated Ion Channels

Answer 1

• Local anesthetics: all local anesthetics bind to intracell site
• Benzodiazepines: hyperpolarize GABAaR
• Ligand can either be:
  
  • extracell mediator: ACh, GABA, aspartate or glutamate
  • intracell: Ca2+, cAMP or cGMP

Question 2

Drugs affecting G Protein-linked Receptors

Answer 2

• Albuterol, a β2-agonist, is used for asthma.
• Propranolol, a β-antagonist, is used for hypertension.
• Bethanechol, a muscarinic agonist, is used for atonic bladder.
• Ipratropium, a muscarinic antagonist, is used for asthma.

Question 3

cAMP-Mediated Hormonal Responses

Answer 3

• Breakdown of glycogen in liver: β-adrenoceptors & glucagon receptors
• Breakdown of TAGs in adipose tissue: β-adrenoceptors
• Increased heart rate and contraction force: β-adrenoceptors
• Relaxation of smooth muscle: β-adrenoceptors

Question 4

Ca2+-mediated responses

Answer 4

• Smooth muscle contraction
• Increased force of contraction of cardiac muscle
• Secretion from exocrine glands
• Neurotransmitter release from neurons
• Hormone release

Question 5

Ligand-regulated Transmembrane Enzymes

Answer 5

• polypeptides consisting of:
  
  • an extracellular hormone-binding domain and
  • cytoplasmic enzyme domain.
• Tyrosine kinase: insulin, EGFR, NGFR, PDGFR
  
  • Ex. Imantinib,
• serine/threonine kinase,
• guanylyl cyclase.

Question 6

Cytokine Receptors

Answer 6

• Cytokine receptors respond to many peptide ligands, such as growth hormone, prolactin, erythropoietin, and interferons.
• no intrinsic enzymatic activity
• bind an intracellular JAK -> STAT/STAT dimers translocate to the nucleus where they regulate transcription of specific genes.

Question 7

Statins

Answer 7

• HMG CoA reductase inhibitor -> By inhibiting cholesterol synthesis statins deplete intracellular supply of cholesterol.
• Depletion of intracellular cholesterol leads to up-regulation of LDL receptors in hepatocytes -> increased clearance of LDL from the blood.

Question 8

Structural Proteins Drug

Answer 8

vinca alkaloids bind to tubulin

Question 9

Actions of Drugs Not Mediated by Binding to Receptors

Answer 9

• Antacids
• Mesna
• Mannitol
• Cholestyramine
• Dimercaprol

Question 10

Extracell enzymes

Answer 10

• ACE found in blood
• ACE inhibitors inhibit formation of AT II to Rx sodium & water retention & lower BP
• Ex. Captopril

Question 11

Mesna

Answer 11

• Mesna mops up acroleine
• Reacts in the bladder with acroleine, a metabolite of the anticancer drug cyclophosphamide, thus preventing hemorrhagic cystitis.

Question 12

Mannitol

Answer 12

increases the osmolarity of various body fluids. This effect can promote diuresis or reduction of cerebral edema.

Question 13

Cholestyramine, colestipol and colesevelam

Answer 13

Bind bile acids in the intestinal lumen and prevent their reabsorption. Used to treat hyperlipidemia.

Question 14

Dimercaprol

Answer 14

chelates heavy metals.

Question 15

Graded Dose-Response Curves

Answer 15

hyperbolic curve according to the following equation:

Question 16

Receptor Binding of Drugs

Answer 16

Question 17

Irreversible Competitive Antagonism drug examples

Answer 17

• Phenoxybenzamine: alpha-adrenoceptor blocker for rx pheochromocytoma
• Aspirin
• Omeprazole: PPI
• Some authors refer to this type of antagonism as noncompetitive.
• Ex. Ketamine: NMDAR

Question 18

Noncompetitive Antagonism

Answer 18

• aka allosteric antagonism.
• insurmountable.
• Emax is decreased.

Question 19

Partial agonist

Answer 19

An agonist that has a lower Emax than a full agonist is a partial agonist. (This refers to the question with the graphs showing the dose responses of norepinephrine and Drug X).

Question 20

Nonreceptor antagonists

Answer 20

• Functional: indirect & physiological
• Chemical

Question 21

Indirect Antagonism

Answer 21

• antagonist binds to a macromolecule in the pathway that links the receptor to the effect.
• Ex.a drug that inhibits PKA blocks the effects of a β-adrenoceptor agonist.

Question 22

Physiological Antagonism

Answer 22

One agonist opposes another agonist, but through different receptors.

Ex. Epi & Histamine

Question 23

Chemical Antagonism

Answer 23

protamine, a protein which is positively charged, counteracts the effects of heparin, an anticoagulant that is negatively charged.

Question 24

Drug Selectivity

Answer 24

A drug is selective if there is at least a 10-fold difference between its binding affinity for its first target (the target which mediates the therapeutic effects) versus its second target (which mediates adverse effects).

The greater the difference, the more selective the drug is.

Question 25

Inverse agonist

Answer 25

• reverse the constitutive activity of a receptor.
• famotidine, losartan, metoprolol and risperidone.

Question 26

Quantal Dose-Effect Curves

Answer 26

• based on a graded response (as seen above) or on an all-or-nothing (quantal) response
• plots fraction of the population